Epigenomic translocation of H3K4me3 broad domains over oncogenes following hijacking of super-enhancers
- Aneta Mikulasova1,
- Daniel Kent1,2,
- Marco Trevisan-Herraz1,
- Nefeli Karataraki2,
- Kent T.M. Fung2,
- Cody Ashby3,
- Agata Cieslak4,
- Shmuel Yaccoby5,
- Frits van Rhee5,
- Maurizio Zangari5,
- Sharmilan Thanendrarajan5,
- Carolina Schinke5,
- Gareth J. Morgan6,
- Vahid Asnafi4,
- Salvatore Spicuglia7,8,
- Chris A. Brackley9,
- Anne E. Corcoran10,
- Sophie Hambleton2,11,
- Brian A. Walker12,
- Daniel Rico1,13 and
- Lisa J. Russell2,13
- 1Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom;
- 2Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom;
- 3Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA;
- 4Université de Paris (Descartes), Institut Necker-Enfants Malades (INEM), Institut National de la Santé et de la Recherche Médicale (Inserm) U1151, and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades, 75015 Paris, France;
- 5Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA;
- 6NYU Langone Medical Center, Perlmutter Cancer Center, NYU Langone Health, New York, New York 10016, USA;
- 7Aix-Marseille University, Inserm, Theories and Approaches of Genomic Complexity (TAGC), UMR1090, 13288 Marseille, France;
- 8Equipe Labellisée Ligue Contre le Cancer, 13288 Marseille, France;
- 9SUPA, School of Physics and Astronomy, University of Edinburgh, Edinburgh EH9 3FD, United Kingdom;
- 10Lymphocyte Signalling and Development Programme, Babraham Institute, Cambridge CB22 3AT, United Kingdom;
- 11Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, United Kingdom;
- 12Melvin and Bren Simon Comprehensive Cancer Center, Division of Hematology Oncology, Indiana University, Indianapolis, Indiana 46202, USA
-
↵13 These authors contributed equally to this work.
Abstract
Chromosomal translocations are important drivers of haematological malignancies whereby proto-oncogenes are activated by juxtaposition with enhancers, often called enhancer hijacking. We analyzed the epigenomic consequences of rearrangements between the super-enhancers of the immunoglobulin heavy locus (IGH) and proto-oncogene CCND1 that are common in B cell malignancies. By integrating BLUEPRINT epigenomic data with DNA breakpoint detection, we characterized the normal chromatin landscape of the human IGH locus and its dynamics after pathological genomic rearrangement. We detected an H3K4me3 broad domain (BD) within the IGH locus of healthy B cells that was absent in samples with IGH-CCND1 translocations. The appearance of H3K4me3-BD over CCND1 in the latter was associated with overexpression and extensive chromatin accessibility of its gene body. We observed similar cancer-specific H3K4me3-BDs associated with hijacking of super-enhancers of other common oncogenes in B cell (MAF, MYC, and FGFR3/NSD2) and T cell malignancies (LMO2, TLX3, and TAL1). Our analysis suggests that H3K4me3-BDs can be created by super-enhancers and supports the new concept of epigenomic translocation, in which the relocation of H3K4me3-BDs from cell identity genes to oncogenes accompanies the translocation of super-enhancers.
Footnotes
-
[Supplemental material is available for this article.]
-
Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.276042.121.
-
Freely available online through the Genome Research Open Access option.
- Received July 30, 2021.
- Accepted December 15, 2021.
This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
